The goal is to discover novel selective CNS penetrant antagonists of the GRP receptor (GRPR) as probes to validate a new target implicated in pruritic responses. In this work, new compounds will be identified utilizing our assay cascade incorporating in vitro receptor pharmacology and novel in vivo screening tools for evaluating pruritic behavior. Candidate ligands will be designed and synthesized using a series of recognized approaches in medicinal chemistry to have a high likelihood of CNS penetration. Compounds that meet our in vitro criteria will be assessed in a series of pre-clinical pruritis models to evaluate the role of this receptor in pruritis. This work will determine the involvement of GRPR in the pruritic response and determine its utility as a potential drug target. PUBLIC HEALTH RELEVANCE: The objective is to discover and develop new probes for the validation of a new mechanism in pruritis, a leading cause of discomfort.